Dasatinib Salt Crystalline Forms for Aqueous Solubility
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Solution Overview
Problem
Dasatinib monohydrate has poor solubility in aqueous mediums, limiting its bioavailability and the routes of administration, and existing salts are unsuitable for pharmaceutical applications due to morphological uniformity and stability issues, making them challenging for industrial-scale production.
Innovation Solution
Development of new salts of dasatinib, specifically cyclamic acid, hydrogen bromide, methane sulfonic acid, and p-toluenesulfonic acid salts, which exhibit improved solubility, stability, and morphological uniformity, including anhydrous and hydrated forms, to enhance bioavailability and suitability for pharmaceutical formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dasatinib monohydrate is used, then the compound has adequate chemical stability, but it exhibits poor solubility in aqueous mediums limiting bioavailability
Solution Approach 1:
The patent applies parameter changes by converting dasatinib monohydrate into different salt forms (hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, benzoate, tosylate, mesylate, trifluoroacetate, oxalate, and fumarate salts). Each salt form has different solubility characteristics while maintaining the core dasatinib structure, thereby improving aqueous solubility without sacrificing chemical stability. The salt formation process changes the chemical parameters of the compound to achieve better bioavailability.
2Quantity of substance
If existing dasatinib salts are used, then some solubility improvement is achieved, but they exhibit morphological uniformity and stability issues unsuitable for pharmaceutical applications
Solution Approach 1:
The patent replaces the problematic mechanical/crystalline structure of existing salts with newly formulated salts that have superior morphological properties. By systematically testing and selecting from multiple salt forms, the invention identifies salts that provide both improved solubility and adequate morphological uniformity, replacing the inadequate existing salt forms with optimized alternatives suitable for pharmaceutical manufacturing.
3Reliability
If dasatinib base monohydrate is used, then the compound maintains chemical stability, but its poor solubility restricts routes of administration and pharmaceutical formulation preparation
Solution Approach 1:
The patent enhances the versatility of dasatinib by creating multiple salt forms that can accommodate different pharmaceutical formulation requirements and routes of administration. The diverse salt forms (hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, benzoate, tosylate, mesylate, trifluoroacetate, oxalate, and fumarate salts) provide universal applicability across different administration routes (oral, parenteral, topical) and formulation types, while each maintains the necessary chemical stability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new dasatinib salts demonstrate higher stability and improved solubility profiles, particularly at relevant pH values, enabling better bioavailability and suitability for pharmaceutical compositions, addressing the limitations of existing dasatinib monohydrate forms.
Implementation Method 1
new salts of dasatinib of formula (1) which are more soluble in aqueous medium than the dasatinib (monohydrate) base
Implementation Method 2
Crystalline n-butanol solvate (BU-2) and crystalline monohydrate (H1-7) of dasatinib are disclosed
Data Source
AI summary
The invention relates to normal or acidic salts of dasatinib and the hydrate and solvate forms thereof. More specifically the invention concerns: dasatinib cyclamic acid salt, dasatinib cyclamic acid (1:1) salt Form I, dasatinib cyclamic acid (1:1) salt Form II, dasatinib hydrogen bromide (1:2) salt, dasatinib methane sulfonic acid (1:2) salt, dasatinib p-toluenesulfonic acid (1:1) dihydrate salt, anhydrous dasatinib p-toluenesulfonic acid (1:1) salt Form I, anhydrous dasatinib p-toluenesulfonic acid (1:1) salt Form II, dasatinib p-toluenesulfonic acid (1:1) salt methanol solvate. Moreover the invention relates process for preparing dasatinib salts, pharmaceutical compositions comprising thereof and the use of dasatinib salts the treatment of cancer.